PROJECT SUMMARY/ABSTRACT Title: B cell antigen receptor (BCR)-driven mechanistic connection between B cell lymphomagenesis and autoimmunity Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of malignancies affecting lymphocytes. Collectively, NHL are the fifth most common cancers in the US, and more than 90% of NHL are of B cell origin. There are roughly equal number of T and B cells in spleen and more T cells in lymph nodes. Why are B cells so prone to lymphomagenesis? This is probably due to B cell-specific DNA mutagenesis processes, somatic hypermutation (SHM) and class switch recombination (CSR). SHM/CSR are initiated by activation-induced deaminase (AID) and are required to produce high affinity isotype-switched antibodies (Abs) that are essential for immunity against pathogens. However, B cells pay a high price for utilizing AID to generate point mutations or DNA double-stranded breaks (DSBs) during SHM/CSR. AID is a genome mutator and, if dysregulated, can cause genome-wide DSBs that lead to chromosomal translocations and lymphomas. Hence, AID expression is tightly controlled and only occurs in activated B cells during infection or immunization. B cell antigen receptor (BCR) is essential for B cell survival and for recognizing specific antigens including self-antigens. However, signaling by the BCR alone cannot induce AID expression and CSR in vitro, and it is unclear whether BCR activation by antigen alone can induce AID expression in vivo. Why is it such an important question to be addressed? Because this may serve as a protective mechanism to keep self-reactive B cells from turning cancerous. If antigen alone could induce AID expression in the absence of pathogen- associated co-stimulation, B cells might generate harmful auto-antibody responses, given the abundance of self-antigens in our body. Chronic activation of BCR by such self-antigens will lead to survival and proliferation of B cells, which, together with abnormally induced AID expression, would significantly increase the likelihood of tumorigenesis. Hence, understanding the role of BCR signaling in AID regulation is highly significant, with important implications for autoimmunity and B cell lymphomagenesis as well as the mechanistic connection between these two pathological conditions. In this proposal, we will elucidate what factors regulate the ability of BCR to induce AID expression, genomic instability and lymphomagenesis in B cells.